Complement receptor type 2 (CR2/CD21) is a cell surface receptor that functions in diverse biological processes that include activating B-cell and T-dependent humoral immune responses, maintaining long-term B-cell memory and mediating the development of B-cell tolerance to self-antigen. CR2 carries out these diverse functions by interacting with different ligands. Additionally, CR2 is also the receptor for a virus ligand: EBVgp35O. One of the fundamental questions is: what is the structural basis for the recognition of CR2 by these different ligands in order to generate different downstream signals for a particular function. Our goal is to provide answers to this fundamental biological question, which also bears significant medical relevance because both CR2 malfunction and EBV infection are associated with important human diseases such as autoimmune diseases, lymphomas and carcinomas. Four specific aims are built upon our recent success in the structural studies of CR2-C3d interactions. Aim 1: The crystal structure of CR2 containing SCR 1-4 will be determined to learn the SCR domain structure and orientation that will provide insight into the ligand-binding specificity and diversity of CR2. Aim 2: The domain(s) of gp350 important in binding to CR2 will be determined using molecular genetic and biochemical methods. Aim 3: The crystal structure of CR2 binding to gp350 will be determined to understand the initial step of EBV infection and to extend our knowledge of diversity of CR2-ligand interactions. The structure will identify the detailed bonding contact between CR2 and gp350, which is known to be non-identical from those in the CR2-C3d complex. Aim 4: The structure-guided mutagenesis of gp350 will be performed to generate mutant gp350 as well as mutant EBV virus to probe the EBV-CR2 interactions in more details. At the same time, phage peptide library will be employed to screen for peptide ligands for gp350 that can specifically inhibit the binding of gp350 with CR2. These specific aims outline an interdisciplinary approach to increase our understanding of the functions of CR2 and its interactions with various ligands. The results will likely provide a basis for designing drugs to treat the diseases associated with CR2 malfunctions and EBV infection.